ABSTRACT
Background: Cannabidiol (CBD), extracted from Cannabis sativa, has anticancer, anti-inflammation, and analgesic effects. Nevertheless, its therapeutic effect and the mechanism by which it alleviates oral mucositis (OM) remain unclear. Aims: To explore the impact of CBD on OM in mice and on human oral keratinocyte (HOK) cells. Study Design: Expiremental study. Methods: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, GeneCard, DisGeNET, and Gene Expression Omnibus databases were used to conduct therapeutic target gene screening for drugs against OM. Cytoscape software was used to build networks linking components, targets, and diseases. The STRING database facilitated analysis of intertarget action relationships, and the target genes were analyzed for Kyoto Encyclopedia of Genes and Genomes pathway enrichment. Occurrence of serum inflammation-related factors, hematoxylin and eosin staining, and immunohistochemistry were used to assess OM injury. Cell proliferation, migration, pyroptosis, and apoptosis of HOK cells under different treatments were assessed. Molecular mechanisms were elucidated through western blot and quantitative real-time polymerase chain reaction analyses. Results: A total of 49 overlapping genes were pinpointed as potential targets, with NF-κB1, PIK3R1, NF-κBIA, and AKT1 being recognized as hub genes among them. Additionally, the PI3K/Akt/NF-κB and interleukin-17 signaling pathways were identified as relevant. Our in vivo experiments showed that CBD significantly reduced the proportion of lesion area, mitigated oral mucosal tissue lesions, and downregulated the expression levels of genes and levels of proteins, including NLRP3, P65, AKT, and PI3K. In vitro experiments indicated that CBD enhanced HOK cell proliferation and migration and reduced apoptosis through inhibition of the PI3K/Akt/NF-κB signaling pathway and pyroptosis. Conclusion: Our findings suggest a novel mechanism for controlling OM, in which CBD suppresses the PI3K/Akt/NF-κB signaling pathway and pyroptosis, thereby mitigating OM symptoms.
Subject(s)
Cannabidiol , NF-kappa B , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Pyroptosis , Stomatitis , Cannabidiol/pharmacology , Cannabidiol/therapeutic use , Animals , Pyroptosis/drug effects , Mice , Stomatitis/drug therapy , NF-kappa B/drug effects , NF-kappa B/analysis , Phosphatidylinositol 3-Kinases/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Humans , Signal Transduction/drug effects , Disease Models, AnimalABSTRACT
In this work, chitosan (CS) decorated metronidazole (MTZ) microcapsules (CS@MTZ) were synthesized and used as a cross-linker for the preparation of a poly(vinyl alcohol) (PVA) injectable hydrogel by dynamic covalent bonding and ionic interaction through a 4-carboxyphenylboronic acid bridge. The use of MTZ microcapsules efficiently slowed down the release rate of the hydrophilic antibiotic from the hydrogel matrix. Besides, the hydrophobicity of the microcapsules endows the PVA@CS@MTZ hydrogel to be sticky to a substrate in wet conditions, under a suggested mechanism of evicting the water boundary layer on the substrate. The sustained release behavior endowed a prolonged bacteriostasis ability of the hydrogel formulation for up to 14 days in vitro, and the bioadhesive property as well as the injectability of the hydrogel benefited the topical delivery of MTZ in periodontal pockets and exhibited desirable antibacterial capacity in 1 week on the rat periodontitis model.
